Discovery of Novel Cytotoxic Agents for Advanced Melanoma While melanoma in early stages can usually be cured by surgical removal, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of research, Dacarbazine (DTIC) still remains the only FDA approved drug to treat advanced melanoma, yet it only provides complete remission in less than 5% of patients. With the rapidly rising incidents of melanoma in the United States, there is an urgent need to develop novel chemotherapeutic agents for this disease. We recently identified three potent lead compounds against melanoma in vitro. Unlike DTIC, these molecules are not alkylation agents. Most likely they interfere with growth factors and other molecules involved in the cancer cell's signaling pathways. The most potent lead compounds have IC50 values in the sub-micromole range with over 10 fold selectivity against cancer cells. Compared with the drug Sorafenib which showed promising effects for melanoma treatment in clinical trials, these novel compounds are more potent and more selective. The mechanisms of action of these compounds are likely to be different from existing anticancer drugs such as DTIC, Taxol, or Sorafenib. In this proposal, we plan to perform extensive synthesis and SAR studies to further optimize the potency and selectivity of these compounds. Our central hypothesis is that new analogs of our lead structures could achieve better selectivity than existing drugs used in clinical trials, while possessing much higher potency towards melanoma. Our specific aims are: (1) to synthesize focused sets of thiazolidine analogs, followed by extensive structure activity relationships (SAR) studies for lead optimization; (2) parallel to the synthetic efforts and biological testing, to use combinations of analytical techniques in both biology and chemistry to investigate the possible mechanisms of action and verify the drug targets for these novel compounds. High resolution magic angle spinning NMR (HR-MAS NMR) and other advanced analytical techniques will be used for global analysis of adaptive metabolic responses in an analogous fashion to genomics and proteomics experiments. The ultimate goal for this project is to synthesize and identify sets of the most promising compounds having novel mechanisms of actions for further in vivo development. PUBLIC HEALTH RELEVANCE: There is currently no curative therapy for advanced melanoma; available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to synthesize novel classes of compounds as potential therapeutic agents. Studies proposed herein are designed to test the hypothesis that the activity of these compounds will have improved efficacy and can be optimized and provide the groundwork for the development of a new class of therapeutic agents to treat advanced aggressive melanoma. This is a high risk, innovative proposal to discover a non-surgical means for a more selective and curative pharmacologic therapy for advanced melanoma. [unreadable] [unreadable] [unreadable]